A novel survival model of cardioplegic arrest and cardiopulmonary bypass in rats: a methodology paper

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Discussion
Research focusing on cardioprotective strategies during cardiac surgery has been hindered by the lack of a suitable small animal model that would allow for complete cardioplegic arrest with good survivability. Most previous research was performed in isolated heart models 101415. While these models allowinvestigating the immediate effects of therapeutic interventions or different cardioplegia solutions, they preclude the assessment of long-term histological, biochemical, or functional outcomes. Survival studies using dogs 132324 or pigs 25 have been performed but are limited due to sample size and costs. Although a number of rat CPB models have been described over the years 2627282930, all of them were resembling beating heart CPB, and none of them included any form of aortic crossclamping and antegrade cardioplegia administration. To our knowledge, only one small animal cardioplegic arrest model has been described so far 31. In their paper, G─é─¢nzinger et al. describe a rat model in which cardioplegic arrest is achieved by injecting a cardioplegic solution into the aortic through a sternotomy while at the same time the branchiocephalic trunk and aortic arch are occluded by tourniquets. Blood loss during the procedure is significant. Compared to our model, this previously described model is not a survival model as it includes full sternotomy (preferably avoided in small four-legged animals), and carotid arteries and jugular veins are cannulated. Therefore, we describe a novel in vivo survival CPB model that allows minimal invasive administration of antegrade cardioplegia with endoaortic crossclamping with resulting cardioplegic arrest in rats.

Due to the excellent survivability and ease of postoperative cardiac recovery, this model lends itself to the investigation of genomic and proteomic changes as well as histological alterations that can be assessed at any time point and new therapeutic interventions aiming to optimize cardioprotection. Over the last several years, substantial preclinical advances have been made in gene- or cell-based therapies for myocardial protection and in rescue strategies for myocardial ischemia-reperfusion injury, all aimed to employ different types of genes, vectors, and delivery routes 3233. Among these, cardiac gene delivery methods with the use of CPB, in which the adenoviral vector is administered following cardioplegic arrest, allow prolonged myocardial exposure time to the adenoviral vector and improved gene transfer 1617. We speculate that the model described here will, therefore, facilitate direct intracoronary administration of medications, gene vectors, or cells and might even allow for ultrasoundmediated gene transfer. Because exposure time and coronary flow are major determinants of efficient intracoronary delivery, complete cardioplegic arrest with negligible coronary flow and long wash-in periods will likely optimize delivery and limit extracardiac expression 1617.

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